Dietary nitrate improves age-related hypertension and metabolic abnormalities in rats via modulation of angiotensin II receptor signaling and inhibition of superoxide generation

Free Radic Biol Med. 2016 Oct:99:87-98. doi: 10.1016/j.freeradbiomed.2016.07.025. Epub 2016 Jul 26.


Advanced age is associated with increased risk for cardiovascular disease and type 2 diabetes. A proposed central event is diminished amounts of nitric oxide (NO) due to reduced generation by endothelial NO synthase (eNOS) and increased oxidative stress. In addition, it is widely accepted that increased angiotensin II (ANG II) signaling is also implicated in the pathogenesis of endothelial dysfunction and hypertension by accelerating formation of reactive oxygen species. This study was designed to test the hypothesis that dietary nitrate supplementation could reduce blood pressure and improve glucose tolerance in aged rats, via attenuation of NADPH oxidase activity and ANG II receptor signaling. Dietary nitrate supplementation for two weeks reduced blood pressure (10-15mmHg) and improved glucose clearance in old, but not in young rats. These favorable effects were associated with increased insulin responses, reduced plasma creatinine as well as improved endothelial relaxation to acetylcholine and attenuated contractility to ANG II in resistance arteries. Mechanistically, nitrate reduced NADPH oxidase-mediated oxidative stress in the cardiovascular system and increased cGMP signaling. Finally, nitrate treatment in aged rats normalized the gene expression profile of ANG II receptors (AT1A, AT2, AT1A/AT2 ratio) in the renal and cardiovascular systems without altering plasma levels of renin or ANG II. Our results show that boosting the nitrate-nitrite-NO pathway can partly compensate for age-related disturbances in endogenous NO generation via inhibition of NADPH oxidase and modulation of ANG II receptor expression. These novel findings may have implications for nutrition-based preventive and therapeutic strategies against cardiovascular and metabolic diseases.

Keywords: Aging; Angiotensin II receptors; Endothelial dysfunction; Hypertension; Metabolic syndrome; NADPH oxidase; Nitric oxide; Nitrite; Renin; Superoxide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Aging / genetics
  • Aging / metabolism*
  • Angiotensin II / blood
  • Angiotensin II / genetics
  • Animals
  • Blood Pressure / drug effects*
  • Cyclic GMP / blood
  • Dietary Supplements*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Gene Expression Regulation
  • Glucose Tolerance Test
  • Hypertension / blood
  • Hypertension / genetics
  • Hypertension / physiopathology
  • Hypertension / prevention & control*
  • Male
  • Mesenteric Arteries / drug effects
  • Mesenteric Arteries / metabolism
  • NADPH Oxidases / antagonists & inhibitors
  • NADPH Oxidases / blood
  • NADPH Oxidases / genetics
  • Nitrates / administration & dosage*
  • Nitrates / blood
  • Nitric Oxide Synthase Type III / blood
  • Nitric Oxide Synthase Type III / genetics
  • Nitrites / blood
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Angiotensin / blood*
  • Receptors, Angiotensin / genetics
  • Signal Transduction
  • Tissue Culture Techniques


  • Nitrates
  • Nitrites
  • Receptors, Angiotensin
  • Angiotensin II
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • NADPH Oxidases
  • Cyclic GMP
  • Acetylcholine